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The Journal of Neuroscience, February 16, 2005, 25(7):1778-1787; doi:10.1523/JNEUROSCI.4249-04.2005

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Neurobiology of Disease
Triple Knock-Out of CNTF, LIF, and CT-1 Defines Cooperative and Distinct Roles of these Neurotrophic Factors for Motoneuron Maintenance and Function

Bettina Holtmann,¹ Stefan Wiese,¹ Mohtashem Samsam,² Katja Grohmann,¹ Diane Pennica,³ Rudolf Martini,² and Michael Sendtner¹

¹The Institute for Clinical Neurobiology and ²Section of Developmental Neurobiology, Department of Neurology, D-97080 Wuerzburg, Germany, and ³Molecular Oncology, Genentech, South San Francisco, California 94080

Members of the ciliary neurotrophic factor (CNTF)-leukemia inhibitory factor (LIF) gene family play an essential role for survival of developing and postnatal motoneurons. When subunits of the shared receptor complex are inactivated by homologous recombination, the mice die at approximately birth and exhibit reduced numbers of motoneurons in the spinal cord and brainstem nuclei. However, mice in which cntf, lif, or cardiotrophin-1 (ct-1) are inactivated can survive and show less motoneuron cell loss. This suggests cooperative and redundant roles of these ligands. However, their cooperative functions are not well understood. We generated cntf/lif/ct-1 triple-knock-out and combinations of double-knock-out mice to study the individual and combined roles of CNTF, LIF and CT-1 on postnatal motoneuron survival and function. Triple-knock-out mice exhibit increased motoneuron cell loss in the lumbar spinal cord that correlates with muscle weakness during early postnatal development. LIF deficiency leads to pronounced loss of distal axons and motor endplate alterations, whereas CNTF-and/or CT-1-deficient mice do not show significant changes in morphology of these structures. In cntf/lif/ct-1 triple-knock-out mice, various degrees of muscle fiber type grouping are found, indicating that denervation and reinnervation had occurred. We conclude from these findings that CNTF, LIF, and CT-1 have distinct functions for motoneuron survival and function and that LIF plays a more important role for postnatal maintenance of distal axons and motor endplates than CNTF or CT-1.

Key words: CNTF; LIF; CT-1; motoneuron; skeletal muscle; motor endplates

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Received Oct 13, 2004; revised December 20, 2004; accepted December 22, 2004.

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